Gastrointestinal Hyperplasia with Altered Expression of DNA Polymerase β

Background: Altered expression of DNA polymerase β (Pol β) has been documented in a large percentage of human tumors. However, tumor prevalence or predisposition resulting from Pol β over-expression has not yet been evaluated in a mouse model. Methodology/Principal Findings: We have recently developed a novel transgenic mouse model that over-expresses Pol β. These mice present with an elevated incidence of spontaneous histologic lesions, including cataracts, hyperplasia of Brunner's gland and mucosal hyperplasia in the duodenum. In addition, osteogenic tumors in mice tails, such as osteoma and osteosarcoma were detected. This is the first report of elevated tumor incidence in a mouse model of Pol β over-expression. These findings prompted an evaluation of human gastrointestinal tumors with regard to Pol β expression. We observed elevated expression of Pol β in stomach adenomas and thyroid follicular carcinomas, but reduced Pol β expression in esophageal adenocarcinomas and squamous carcinomas. Conclusions/Significance: These data support the hypothesis that balanced and proficient base excision repair protein expression and base excision repair capacity is required for genome stability and protection from hyperplasia and tumor formation

Incidence of non-neoplastic lesions observed in DNA polymerase β Tg mice.

*<p>Frequency defined as the number of animals with the lesion divided by the number of animals with the tissue examined histopathologically, multiplied by 100. Abnormal non-neoplastic changes were not detected in thyroid, parathyroid, thymus, stomach, jejunum, ileum, cecum, colon and pituitary.</p

Incidence of non-neoplastic & neoplastic proliferative lesions in DNA polymerase β Tg mice.

*<p>Frequency defined as the number of animals with the lesion divided by the number of animals with the tissue examined histopathologically, multiplied by 100. Data derived from 15 males and 21 females except where noted. No neoplastic changes were detected in gallbladder, parathyroid, thymus, ileum, cecum, colon, pancreas, brain, eye, urinary bladder, testis, epididymis, prostate, seminal vesicle, oviduct, vagina, and mammary gland.</p

Incidence of macroscopic findings observed in DNA polymerase β Tg mice.

*<p>Frequency defined as the number of animals with the lesion divided by the number of animals with the tissue examined macroscopically, multiplied by 100.</p

Representative photomicrographs (H & E stain) of duodenal changes in Pol β Tg mice.

<p>(A) Normal duodenum. Note normal Brunner's glands (arrows) (magnification×20). (B) Diffuse hyperplasia of Brunner's glands (small arrows) and duodenal crypt epithelium (large arrow). Note markedly increased mucosal thickness due to glandular hyperplasia, compared to panel A (magnification×20). (C) Cystic dilatation of mucosal crypts and Brunner's glands with displacement of cystic glands into the tunica muscularis (magnification×200). (D) Focal proliferation of dysplastic glands in a mouse diagnosed with duodenal adenoma (magnification×400).</p

Decreased expression of Pol β in human esophageal adenocarcinoma.

<p>(A) Photomicrograph of sections of esophageal adenocarcinoma and esophageal squamous mucosa stained for Pol β expression by immunohistochemistry. Top images reflect magnification×40 and the inserts depict magnification×100. (B) Bar graph representing relative expression level of Pol β in various tumors (stippled, open bars) and pathologically normal (grey bars) epithelial tissues. Immunoreactivity Score is the average of 5 different tumor samples each evaluated in two independent analyses.</p